Natriuretic polypeptides are polypeptides that can cause natriuresis—increased sodium excretion in the urine. Such polypeptides can be produced by brain, heart, kidney, and/or vascular tissue. The natriuretic polypeptide family in humans includes the cardiac hormones atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin (URO). Natriuretic polypeptides function via well-characterized guanylyl cyclase receptors (i.e., NPR-A for ANP, BNP, and URO; and NPR-B for CNP) and the second messenger cyclic 3′5′ guanosine monophosphate (cGMP) (Kuhn (2003) Circ. Res. 93:700-709; Tawaragi et al. (1991) Biochem. Biophys. Res. Commun. 175:645-651; and Komatsu et al. (1991) Endocrinol. 129:1104-1106).
Cardiac arrhythmia includes a heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart may beat too quickly or too slowly, and may be regular or irregular. Atrial fibrillation is a common arrhythmia that is familial in a small subset of cases. Atrial fibrillation is the most common sustained cardiac arrhythmia, constituting a growing epidemic in the aging population with a 25% lifetime risk (Braunwald (1997) N. Engl. J. Med. 337:1360-1369; and Lloyd-Jones et al. (2004) Circulation 110:1042-1046). It develops as a paroxysmal disorder characterized by rapid, irregular electrical activation of the atria and can be associated with palpitations, syncope, thromboembolic stroke, and congestive heart failure. Valvular, ischemic, hypertensive, and myopathic heart disease are the most common causes of acquired atrial fibrillation. A genetic basis for atrial fibrillation also is evident in population-based studies (Fox et al. (2004) JAMA 291:2851-2855; and Gudbjartsson et al. (2007) Nature 448:353-357) and in a subset of patients with familial disease (Brugada et al. (1997) N. Engl. J. Med. 336:905-911; and Darbar et al. (2003) J. Am. Coll. Cardiol. 41:2185-2192). Human genetic investigations have identified atrial fibrillation-associated mutations in cardiac ion channels (Chen et al. (2003) Science 299:251-254; Olson et al. (2005) JAMA 293:447-454; and Olson et al. (2006) Hum. Mol. Genet. 15: 2185-2191) and gap junction proteins (Gollob et al. (2006) N. Engl. J. Med. 354:2677-2688), implicating myocellular derangements in ion flux. The molecular basis of atrial fibrillation remains unknown, however, in the majority of cases.